Raltegravir Switch Study to Reduce Liver Fibrosis Progression in HIV-Hepatitis C Co-infection

The recruitment status of this study is unknown because the information has not been verified recently.
Verified August 2012 by McGill University Health Center.
Recruitment status was  Recruiting
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
CIHR Canadian HIV Trials Network
Information provided by (Responsible Party):
Marina Klein, McGill University Health Center
ClinicalTrials.gov Identifier:
NCT01231685
First received: October 29, 2010
Last updated: August 15, 2012
Last verified: August 2012
  Purpose

HIV infection exerts a negative impact on the course of HCV infection. Co-infected individuals progress more rapidly to liver fibrosis, cirrhosis and ESLD compared to those infected with HCV alone. Some of the this accelerated fibrosis may be related to longterm chronic toxicity from protease inhibitor based ART.

Hypothesis: Switching from ritonavir boosted-PI based ART regimen to a Raltegravir-based regimen will reduce the rate of hepatic fibrosis progression in HIV-HCV co-infected patients as measured by transient elastography (Fibroscan®) and the AST-to-platelet ratio index (APRI).


Condition Intervention Phase
HIV
Hepatitis C
Liver Fibrosis
Drug: Raltegravir
Drug: Ritonavir-boosted protease inhibitor
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Prospective Open Label Study of Switching to Raltegravir Based ART Compared to Maintaining Ritonavir Boosted PI-based ART on Liver Fibrosis Progression in HIV-HCV Coinfected Patients

Resource links provided by NLM:


Further study details as provided by McGill University Health Center:

Primary Outcome Measures:
  • To evaluate the effect of switch on change in liver fibrosis score [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]

    Change in fibrosis will be assessed by:

    1. Change in Fibroscan® score (kPa) at 48 weeks from baseline
    2. Change in log transformed AST-to-platelt ratio (APRI) score at 48 weeks from baseline


Secondary Outcome Measures:
  • To evaluate inflammatory markers associated with liver fibrosis [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    As a switch from protease inhibitors based regimen to a raltegravir based regimen may impact the liver through various potential mechanisms, we will explore the impact of treatment switching on inflammatory biomarkers.

  • To evaluate effect of switch on hepatic function [ Time Frame: 72 weeks ] [ Designated as safety issue: Yes ]
    Liver enzymes, albumin, direct bilirubin and INR will be measured at week 0,2,4,8,12,24,36,40 and 72.

  • To evaluate effect of switch on metabolic parameters [ Time Frame: 72 weeks ] [ Designated as safety issue: Yes ]
    Metabolic parameters, such as fasting glucose, lipid and insulin profiles will be measured at week 0,24 and 48 post switch

  • Immunologic and virologic safety [ Time Frame: 72 weeks ] [ Designated as safety issue: Yes ]
    To ensure safety, with respect to control of HIV infection following a switch to raltegravir, HIV viral load and CD4 cell counts will be measured at weeks 0,4,8 12, 24, 36, 48 and 72 post switch.


Estimated Enrollment: 40
Study Start Date: December 2011
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: ritonavir-boosted protease inhibitor Drug: Raltegravir
Subjects will maintain their nucleoside backbone and switch ritonavir-boosted protease inhibitor to Raltegravir 400 mg po BID for 48 weeks.
Other Names:
  • Isentress
  • MK-0518
  • RGV
Drug: Ritonavir-boosted protease inhibitor
Subjects will maintain their nucleoside backbone and remain on a ritonavir-boosted protease inhibitor at standard doses for for 48 weeks
Other Names:
  • Kaletra
  • Lopinavir-ritonavir
  • Atazanavir-ritonavir
  • Reyataz-norvir
  • Darunavir-ritonavir
  • Presista-norvir
Experimental: Raltegravir Drug: Raltegravir
Subjects will maintain their nucleoside backbone and switch ritonavir-boosted protease inhibitor to Raltegravir 400 mg po BID for 48 weeks.
Other Names:
  • Isentress
  • MK-0518
  • RGV
Drug: Ritonavir-boosted protease inhibitor
Subjects will maintain their nucleoside backbone and remain on a ritonavir-boosted protease inhibitor at standard doses for for 48 weeks
Other Names:
  • Kaletra
  • Lopinavir-ritonavir
  • Atazanavir-ritonavir
  • Reyataz-norvir
  • Darunavir-ritonavir
  • Presista-norvir

Detailed Description:

Primary Objective-To assess if switching from ritonavir boosted-PI based ART regimen to a Raltegravir-based regimen will reduce the rate of hepatic fibrosis progression in HIV-HCV co-infected patients as measured by transient elastography (Fibroscan®) and the AST-to-platelet ratio index (APRI) after 48 weeks of treatment.

Secondary Objectives:

(i) To assess the safety and tolerability of switching from a ritonavir boosted-PI ART regimen to a raltegravir-based regimen for 48 weeks.

(ii) To evaluate hepatic function (liver enzymes) at weeks 0, 2, 4, 8, 12, 24, 36, 48 and 72 post switch.

(iii) To evaluate the effect of switching treatment on control of HIV infection (as measured by HIV viral load and CD4) at weeks 0, 4, 8, 12, 24, 36, 48, and 72 post switch.

(iv) To evaluate metabolic profiles (e.g, fasting lipid profiles, glucose and insulin) at weeks 0, 24, 48 and 72 post switch.

(v) To evaluate inflammatory markers associated with liver fibrosis at weeks 0, 2, 4, 8, 12, 24, 36, 48 and 72 post switch.

Population: Patients will be selected from CTN222; a Canadian National multisite prospective cohort of HCV-HIV infected persons (N=978) or from other eligible patients followed at participating sites. All patients recruited into the cohort are adults aged over 16 years old with documented HIV infection (ELISA with western blot confirmation) and with chronic HCV infection or evidence of HCV exposure (e.g. HCV-seropositive by ELISA with RIBA II or EIA confirmation, or if serologically false negative, HCV RNA+).

Study Design: A Randomized Prospective Open label study

Sample Size:

N = 40 This is a Phase II study designed to evaluate the safety and feasibility of a switch to raltegravir in HIV-HCV co-infected patients. As neither the duration of time required to improve fibrosis nor the potential impact of such a switch currently is known, this trial will provide important pilot data with which to estimate the true effect size and calculate the sample size required to conduct a larger definitive study on this question. It is hypothesized that switching therapy will lead to significant reduction in fibrosis as measured by APRI and FibroScan®. In other studies, for example, of successful HCV treatment using FibroScan®, a 34% reduction in fibrosis score was observed in those obtaining a sustained virologic response at 48 weeks (e.g., from mean baseline score of 10.3 kPa to 6.6 kPa at 48 weeks; s.d.= 5 kPa 1). We propose a sample size of 20 patients in each group, which would provide approximately 80% power to detect at least a difference of 5 kPa in fibrosis score change between the two groups assuming a similar standard deviation.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 18 years or older
  2. Chronic HIV-HCV co-infection (HCV RNA + for at least 6 months and could have had previous HCV treatment).
  3. Receiving ritonavir boosted PI-based ART for at least 6 months.
  4. APRI score ≥ 1.5 (equivalent to liver biopsy score of ≥ F2) AND/OR Fibroscan > 6.9KPa
  5. HIV viral suppression (<50 copies/mL) for at least 6 months.
  6. No prior evidence of resistance to raltegravir or co-administered nucleoside backbone.
  7. No prior history of virologic failure.

Exclusion Criteria:

  1. Clinical evidence of decompensated liver disease (e.g., ascites, esophageal varices, or hepatic encephalopathy hepatoma or hepatocellular carcinoma).
  2. Chronic Hepatitis B infection (defined as positive HBsAg or Hepatitis B viral load greater than 10,000 copies/mL).
  3. AFP greater than or equal to 200 ng/mL at screening.
  4. Known or suspected Wilson's disease, alpha-1-antitrypsin deficiency, celiac disease or other cause of chronic liver disease.
  5. Chronic renal insufficiency (eGFR < 20 mL/min) at screening.
  6. Pregnancy and planned pregnancy (WOCBP not using adequate contraception).
  7. Women who are breastfeeding.
  8. Active opportunistic infection (except oral thrush) or neoplasm (except Kaposi's sarcoma, skin cancer, or cancer of the cervix or anus, unless known or suspected liver metastasis).
  9. Patients intending to start HCV therapy within the treatment phase (within the year following the baseline visit).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01231685

Contacts
Contact: Marina B Klein, M.D. M.Sc 514-934-1934 ext 32523

Locations
Canada, British Columbia
Providence Health Care- St. Paul's Hospital Recruiting
Vancouver, British Columbia, Canada, V6Z 1Y6
Contact: Mark Hull, MD    604-806-8832    mhull@cfenet.ubc.ca   
Contact: Gerene Larsen, RN    604 806-8832    glarsen@cfenet.ubc.ca   
Principal Investigator: Mark Hull, MD         
Canada, Ontario
University Health Network - Toronto General Hospital Division Recruiting
Toronto, Ontario, Canada, M5G2N2
Contact: Sharon Walmsley, MD    416-340-3871    sharon.walmsley@uhn.ca   
Contact: Rosemarie J. Clarke, RN    416-340-4800 ext 6723    rosemarie.clarke@uhn.ca   
Principal Investigator: Sharon Walmsley, MD         
Canada, Quebec
Montreal Chest Institute Recruiting
Montreal, Quebec, Canada
Contact: Marina Klein, MD, MSc.    514-934-1934 ext 32090    marina.klein@mcgill.ca   
Contact: Nathalie Paisible, RN    514-934-1934 ext 32537    nathalie.paisible@muhc.mcgill.ca   
Principal Investigator: Marina B Klein, MD. M.Sc.         
Sponsors and Collaborators
McGill University Health Center
Merck Sharp & Dohme Corp.
CIHR Canadian HIV Trials Network
Investigators
Principal Investigator: Marina B Klein, MD. M.Sc. McGill University Health Center
  More Information

Publications:
Responsible Party: Marina Klein, MD, McGill University Health Center
ClinicalTrials.gov Identifier: NCT01231685     History of Changes
Other Study ID Numbers: CTN260
Study First Received: October 29, 2010
Last Updated: August 15, 2012
Health Authority: Canada: Health Canada

Keywords provided by McGill University Health Center:
Liver fibrosis
HIV
Hepatitis C Virus
Coinfection

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Fibrosis
Liver Cirrhosis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Pathologic Processes
Ritonavir
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 29, 2014